Transcriptomics of Pain in Sickle Cell Disease

项目摘要/摘要 镰状细胞病(SCD)患者在频率上表现出明显的个体间异质性。 急性疼痛事件或血管闭塞危象(VOC)和慢性疼痛的发展。结节 VOC的典型特征是白细胞与内皮细胞的粘连，随之而来的是红细胞 脱氧和镰刀状，导致血管闭塞、缺血和疼痛。因此，我们 从CD71+细胞收集SCD患者RNA(仍保留RNA的红细胞前体)和 CD45+，慢性疼痛和非慢性疼痛患者的白细胞，以及纵向采集 在稳态、VOC和VOC分辨率下获得，并将这些样品提交给TOPMed 用于RNAseq分析。我们建议利用这个转录组数据，从一个良好的表型 儿童SCD队列，以解决急性和慢性疾病的客观、可量化标记物未得到满足的需求 慢性疼痛，并在生殖系和体细胞突变的背景下进行评估 受试者的全基因组测序(WGS)数据，也是TOPMed。短期目标为1) 确定在慢性疼痛状态下改变的基因和途径，2)确定转录组的变化 与疼痛事件及其解决方案相关联，3)为 慢性疼痛的发展，以及4)确定哪些变量与慢性疼痛相关 通过转录组广泛的关联研究，发展很可能是原因。长 学期目标是利用这些发现1)开发有针对性的疗法来预防和治疗VOC， 2)治疗SCD慢性疼痛的治疗方法，以及3)区分急性疼痛事件和 慢性疼痛。这样做的能力将使提供商能够适当地管理VOC 具有侵略性，不会无意中混淆慢性疼痛和急性疼痛发作。我们的 无法区分急性和慢性疼痛伤害了我们的患者，因为 VOC治疗的主要手段是通过阿片类药物引起的痛敏加重慢性疼痛。 我们的工作将通过我们的创新转录分析来利用TOPMed样本来识别 慢性疼痛的危险因素、治疗靶点和生物标志物，以改善护理和 SCD患者的生活质量。

PROJECT SUMMARY/ABSTRACT Patients with sickle cell disease (SCD) exhibit marked inter-individual heterogeneity in frequency of acute pain events, or vaso-occlusive crises (VOC) and development of chronic pain. The nidus of a VOC is typically the adhesion of a leukocyte to the endothelium, bringing with it a red cell which deoxygenates and sickles, resulting in vaso-occlusion, ischemia, and pain. We therefore collected SCD patient RNA from CD71+ cells (red cell precursors that still retain RNA) and CD45+, leukocytes from individuals with and without chronic pain, and longitudinal collections obtained at steady state, in VOC, and VOC resolution, and submitted these samples to TOPMed for RNASeq analysis. We propose to leverage this transcriptome data from a well phenotyped pediatric SCD cohort to address the unmet need of objective, quantifiable markers of acute and chronic pain, and evaluate in the context of the germline and somatic mutations found in the same subjects’ whole genome sequencing (WGS) data, also in TOPMed. Short term goals are to 1) identify genes and pathways altered in the chronic pain state, 2) identify transcriptome changes associated with pain events and their resolution, 3) generate a transcriptional risk score for the development of chronic pain, and 4) determine which variants associated with chronic pain development are likely to be causative through transcriptome wide association studies. Long term goals are to use these findings to 1) develop targeted therapies to prevent and treat VOC, 2) therapies to treat chronic pain in SCD, and 3) biomarkers to distinguish acute pain events from chronic pain. The ability to do so will allow providers to manage VOC appropriately and aggressively, without inadvertently confusing chronic pain with an acute pain episode. Our inability to distinguish between acute and chronic pain harms our patients, as the opioids that are the mainstay for VOC treatment often worsen chronic pain through opioid induced hyperalgesia. Our work will leverage TOPMed samples via our innovative transcriptomics analysis to identify risk factors, therapeutic targets, and biomarkers of chronic pain, in order to improve the care and quality of life of individuals living with SCD.